U.S. patent application number 16/469268 was filed with the patent office on 2021-03-25 for orally disintegrated tablet comprising carbamate compound.
This patent application is currently assigned to SK BIOPHARMACEUTICALS CO., LTD.. The applicant listed for this patent is SK BIOPHARMACEUTICALS CO., LTD.. Invention is credited to Myoung Ki BAEK, So Young CHOI, Ji Hye LEE.
Application Number | 20210085646 16/469268 |
Document ID | / |
Family ID | 1000005273668 |
Filed Date | 2021-03-25 |
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United States Patent
Application |
20210085646 |
Kind Code |
A1 |
BAEK; Myoung Ki ; et
al. |
March 25, 2021 |
Orally Disintegrated Tablet Comprising Carbamate Compound
Abstract
The present invention relates to an orally disintegrated tablet
and a method for producing same, the tablet containing a carbamate
compound of chemical formula 1, an isomer thereof, or a
pharmaceutically acceptable salt, a solvate or a hydrate thereof,
as an active ingredient.
Inventors: |
BAEK; Myoung Ki;
(Gyeonggi-do, KR) ; CHOI; So Young; (Gyeonggi-do,
KR) ; LEE; Ji Hye; (Gyeonggi-do, KR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SK BIOPHARMACEUTICALS CO., LTD. |
Gyeonggi-do |
|
KR |
|
|
Assignee: |
SK BIOPHARMACEUTICALS CO.,
LTD.
Gyeonggi-do
KR
|
Family ID: |
1000005273668 |
Appl. No.: |
16/469268 |
Filed: |
December 14, 2017 |
PCT Filed: |
December 14, 2017 |
PCT NO: |
PCT/KR2017/014731 |
371 Date: |
June 13, 2019 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2027 20130101;
A61K 9/2018 20130101; A61K 9/2059 20130101; A61K 9/2054 20130101;
A61K 9/0056 20130101; A61K 31/41 20130101 |
International
Class: |
A61K 31/41 20060101
A61K031/41; A61K 9/20 20060101 A61K009/20; A61K 9/00 20060101
A61K009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 14, 2016 |
KR |
10-2016-0170434 |
Claims
1. An orally disintegrating tablet comprising: (i) a granule
prepared by wet granulation to comprise the following ingredients:
(1) a carbamate compound of the following Formula 1, an isomer
thereof, or a pharmaceutically acceptable salt, solvate or hydrate
thereof as an active ingredient; (2) a hydrophilic excipient
consisting of a first hydrophilic excipient of a sugar alcohol; and
a second hydrophilic excipient selected from the group consisting
of starch, microcrystalline cellulose, hydroxypropylcellulose and
lactose; and (3) a disintegrant; and (ii) a disintegrant which is
mixed with the granule of (i): ##STR00009## wherein, R.sub.1 and
R.sub.2 are each independently selected from the group consisting
of hydrogen, halogen, C.sub.1-C.sub.8 alkyl, halo-C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 thioalkoxy and C.sub.1-C.sub.8 alkoxy; and
one of A.sub.1 and A.sub.2 is CH, and the other is N.
2. The orally disintegrating tablet according to claim 1, wherein
R.sub.1 and R.sub.2 are each independently selected from the group
consisting of hydrogen, halogen and C.sub.1-C.sub.8 alkyl.
3. The orally disintegrating tablet according to claim 1, wherein
the carbamate compound of Formula 1 is carbamic acid
(R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl ester of the
following Formula 2: ##STR00010##
4. The orally disintegrating tablet according to claim 1, wherein
the first hydrophilic excipient of a sugar alcohol is selected from
the group consisting of mannitol, sorbitol, xylitol, lactitol,
maltitol and erythritol.
5. The orally disintegrating tablet according to claim 1, wherein
the disintegrant in the above (i) and (ii) is selected from the
group consisting of sodium starch glycolate, croscarmellose sodium,
low substituted hydroxypropylcellulose and crospovidone.
6. The orally disintegrating tablet according to claim 1, wherein
the content of the carbamate compound is 2.5 wt % to 25 wt % based
on the total weight of the orally disintegrating tablet.
7. The orally disintegrating tablet according to claim 1, wherein
the content of the hydrophilic excipient is 65 wt % to 90 wt %
based on the total weight of the orally disintegrating tablet.
8. The orally disintegrating tablet according to claim 1, wherein
the weight ratio of the first hydrophilic excipient and the second
hydrophilic excipient is 2:1 to 10:1.
9. The orally disintegrating tablet according to claim 1, wherein
the content of the disintegrant in the granule of (i) is 1 wt % to
10 wt % based on the total weight of the orally disintegrating
tablet.
10. The orally disintegrating tablet according to claim 1, the
disintegrant mixed in (ii) contains 60% to 80% of particles having
a particle size of 40 .mu.m to 600 .mu.m, and the content thereof
is 4 wt % to 8 wt % based on the total weight of the orally
disintegrating tablet.
11. The orally disintegrating tablet according to claim 1 for use
in the treatment of anxiety, depression, convulsion, epilepsy,
migraine, bipolar disorder, drug abuse, smoking, attention deficit
hyperactivity disorder (ADHD), obesity, sleep disorders,
neuropathic pain, stroke, cognitive disorders, neurodegeneration or
muscle spasm.
12. A method for preparation of an orally disintegrating tablet,
comprising: (a) a step of mixing the following ingredients (1) to
(3); (1) a carbamate compound of the following Formula 1, an isomer
thereof, or a pharmaceutically acceptable salt, solvate or hydrate
thereof as an active ingredient; (2) a hydrophilic excipient
consisting of a first hydrophilic excipient of a sugar alcohol; and
a second hydrophilic excipient selected from the group consisting
of starch, microcrystalline cellulose, hydroxypropylcellulose and
lactose; and (3) a disintegrant; (b) a step of preparing a granule
by wet granulation using the mixture of step (a); (c) a step of
mixing the granule obtained from step (b) with a disintegrant; and
(d) a step of lubricating and tableting the mixture obtained from
step (c): ##STR00011## wherein, R.sub.1 and R.sub.2 are each
independently selected from the group consisting of hydrogen,
halogen, C.sub.1-C.sub.8 alkyl, halo-C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 thioalkoxy and C.sub.1-C.sub.8 alkoxy; and one of
A.sub.1 and A.sub.2 is CH, and the other is N.
13. The method for preparation according to claim 12, wherein
R.sub.1 and R.sub.2 are each independently selected from the group
consisting of hydrogen, halogen and C.sub.1-C.sub.8 alkyl.
14. The method for preparation according to claim 12, wherein the
carbamate compound of Formula 1 is carbamic acid
(R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl ester of the
following Formula 2: ##STR00012##
15. The method for preparation according to claim 12, wherein the
first hydrophilic excipient of a sugar alcohol is selected from the
group consisting of mannitol, sorbitol, xylitol, lactitol, maltitol
and erythritol.
16. The method for preparation according to claim 12, wherein the
disintegrant in step (a) and step (c) is selected from the group
consisting of sodium starch glycolate, croscarmellose sodium, low
substituted hydroxypropylcellulose and crospovidone.
17. The method for preparation according to claim 12, wherein the
content of the carbamate compound is 2.5 wt % to 25 wt % based on
the total weight of the orally disintegrating tablet.
18. The method for preparation according to claim 12, wherein the
content of the hydrophilic excipient is 65 wt % to 90 wt % based on
the total weight of the orally disintegrating tablet.
19. The method for preparation according to claim 12, wherein the
weight ratio of the first hydrophilic excipient and the second
hydrophilic excipient is 2:1 to 10:1.
20. The method for preparation according to claim 12, wherein the
content of the disintegrant in step (a) is 1 wt % to 10 wt % based
on the total weight of the orally disintegrating tablet.
21. The method for preparation according to claim 12, wherein the
disintegrant in step (c) contains 60% to 80% of particles having a
particle size of 40 .mu.m to 600 .mu.m, and the content thereof is
4 wt % to 8 wt % based on the total weight of the orally
disintegrating tablet.
22. An orally disintegrating tablet prepared by the method
12. ration according to claim 12.
23. The orally disintegrating tablet according to claim 22 for use
in the treatment of anxiety, depression, convulsion, epilepsy,
migraine, bipolar disorder, drug abuse, smoking, attention deficit
hyperactivity disorder (ADHD), obesity, sleep disorders,
neuropathic pain, stroke, cognitive disorders, neurodegeneration or
muscle spasm.
Description
FIELD
[0001] The present invention relates to an orally disintegrating
tablet comprising a carbamate compound of the following Formula 1,
an isomer thereof, or a pharmaceutically acceptable salt, solvate
or hydrate thereof as an active ingredient, and a preparation
method thereof:
##STR00001##
[0002] wherein,
[0003] R.sub.1, R.sub.2, A.sub.1 and A.sub.2 are as defined
herein.
BACKGROUND
[0004] The carbamate compound of Formula 1 and the method for
preparing the same are described in detail in PCT Publication Nos.
WO 2006/112685 A1, WO 2010/150946 A1 and WO 2011/046380 A.sub.2,
the disclosures of which are incorporated herein by reference. One
specific embodiment of the carbamate compound of Formula 1 includes
carbamic acid (R)-1-(2-chlorophenyl)-2-(tetrazol-2-ypethyl ester of
the following Formula 2:
##STR00002##
[0005] The carbamate compound of Formula 1 or 2 is known to be
effective in the treatment of epilepsy.
[0006] Administration of a general immediate-release tablet
containing the carbamate compound of Formula 1 or 2 may be
difficult to take if it is prescribed to epileptic patients who are
afraid to swallow.
[0007] People who are afraid to swallow because of dysphagia or
fear of choking are not confined to young people and older people
but have a wide age distribution, and about 35% of the world's
population are afraid of swallowing. In addition, the development
of a solid formulation that does not need to be swallowed due to
its prompt integration in the oral cavity without water intake is
of great interest to the general population as well as to patients
who have difficulty swallowing, such as elderly persons, infants,
mental patients and uncooperative patients.
[0008] Prescribing medicine for oral administration to people who
are uncomfortable or have trouble in swallowing may cause a
negative effect on the treatment because it may delay or prevent
the consumption of medicine. In addition, in the case of drug for
treating epilepsy, blood concentration of the drug should be
maintained above the therapeutic concentration to prevent further
seizures. If the drug is not administered on time, it cannot
prevent the recurrence of further seizures. Such a situation is
even more fatal because it can lead to an emergency involving
severe nerve damage and after-effects.
[0009] Orally disintegrating tablets are disintegrated within a few
seconds with only a small amount of saliva in the oral cavity, so
it is not necessary to swallow tablets. Hence, medication
compliance of patients who are afraid to swallow can be improved.
Further, as foreign body sensation and residual feeling in the oral
cavity are minimized, it is easier for the patient to adhere to
his/her medication compliance. Therefore, there has been a
continuous demand for developing a manufacturing technique of
orally disintegrating tablet that minimizes foreign body sensation
and residual feeling. However, if the hardness of the tablet is too
low to rapidly disintegrate, the tablets will be easily worn out,
which makes it difficult to transport and store. If the hardness is
made high in order to compensate the above, the disintegration time
in the oral cavity may be delayed. Hence, a manufacturing technique
of an orally disintegrating tablet having appropriate hardness is
necessary.
[0010] The following prior arts are known in the development of
tablets that dissolve or disintegrate in the oral cavity.
[0011] Zydis, an orally disintegrating tablet developed and
commercialized by RP Scherer, has the advantage of being rapidly
disintegrated in the oral cavity. However, since it is prepared
using freeze-drying technology, it is difficult to ensure the
stability of the product during the distribution process due to
physical impact.
[0012] Korean Patent Laid-Open Publication No. 2001-0006835
discloses a method for preparing orally disintegrating tablets by a
direct compression method using spray-dried mannitol as a
disintegrant and crospovidone as a co-disintegrant. However, this
method is disadvantageous in that the dissolution rate in the oral
cavity is relatively lower than those of the above techniques.
[0013] Korean Patent Laid-Open Publication No. 2010-0008419
discloses a method for preparing orally disintegrating tablets
which improves stability by dry mixing of amlodipine after wet
granulation of excipients to improve water instability of
amlodipine. However, in the case of an active ingredient having no
reduction in stability due to moisture, there is a disadvantage in
that a content irregularity may occur due to a difference in
particle size between the wet granule and the active
ingredient.
[0014] Therefore, with regard to the carbamate compound of Formula
1 or 2, in order to improve medication compliance of epileptic
patients who are afraid to swallow the tablets and try to delay or
avoid ingestion of the tablets, it is necessary to develop an
orally disintegrating tablet that exhibits preferable
disintegration rate and hardness, shows uniform content of the
active ingredient and minimizes foreign body sensation and residual
feeling in the oral cavity.
DISCLOSURE
Problem to be Solved
[0015] The present invention is intended to provide an orally
disintegrating tablet and preparation method thereof for improving
medication compliance of patients who are afraid to swallow,
wherein the orally disintegrating tablet comprises a carbamate
compound of Formula 1 or 2 as an active ingredient, exhibits rapid
disintegration in the oral cavity and excellent hardness,
friability and storage stability, and minimizes foreign body
sensation and residual feeling in the oral cavity.
Technical Solution to the Problem
[0016] The present inventors have found that if the granules are
prepared by wet granulation by adding a hydrophilic excipient and a
disintegrant to the carbamate compound of Formula 1 or 2 and then
adding the disintegrant to the granules and mixing them, the
prepared orally integrating tablet shows high hardness and low
friability as well as fast disintegration rate, and also minimizes
foreign body sensation and residual feeling.
[0017] Accordingly, the present invention provides an orally
disintegrating tablet comprising:
[0018] (i) a granule prepared by wet granulation to comprise the
following ingredients: [0019] (1) a carbamate compound of the
following Formula 1, an isomer thereof, or a pharmaceutically
acceptable salt, solvate or hydrate thereof as an active
ingredient; [0020] (2) a hydrophilic excipient consisting of a
first hydrophilic excipient of a sugar alcohol; and a second
hydrophilic excipient selected from the group consisting of starch,
microcrystalline cellulose, hydroxypropylcellulose and lactose; and
[0021] (3) a disintegrant; and
[0022] (ii) a disintegrant which is mixed with the granule of
(i):
##STR00003##
[0023] wherein,
[0024] R.sub.1 and R.sub.2 are each independently selected from the
group consisting of hydrogen, halogen, C.sub.1-C.sub.8 alkyl,
halo-C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 thioalkoxy and
C.sub.1-C.sub.8 alkoxy; and one of A.sub.1 and A.sub.2 is CH, and
the other is N.
[0025] In one embodiment of the present invention, in Formula 1,
R.sub.1 and R.sub.2 are each independently selected from the group
consisting of hydrogen, halogen and C.sub.1-C.sub.8 alkyl.
[0026] In one embodiment, the halo-C.sub.1-C.sub.8 alkyl is
perfluoroalkyl.
[0027] In one embodiment of the present invention, the carbamate
compound of Formula 1 is carbamic acid
(R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl ester of the
following Formula 2:
##STR00004##
[0028] In one embodiment of the present invention, the first
hydrophilic excipient of a sugar alcohol is selected from the group
consisting of mannitol, sorbitol, xylitol, lactitol, maltitol and
erythritol.
[0029] In one embodiment of the present invention, the disintegrant
in the above (i) and (ii) is selected from the group consisting of
sodium starch glycolate, croscarmellose sodium, low substituted
hydroxypropylcellulose and crospovidone.
[0030] Accordingly, in one embodiment, the present invention
provides an orally disintegrating tablet comprising:
[0031] (i) a granule prepared by wet granulation to comprise the
following ingredients: [0032] (1) a carbamate compound of Formula
1, an isomer thereof, or a pharmaceutically acceptable salt,
solvate or hydrate thereof as an active ingredient; [0033] (2) a
hydrophilic excipient consisting of a first hydrophilic excipient
of a sugar alcohol selected from the group consisting of mannitol,
sorbitol, xylitol, lactitol, maltitol and erythritol; and a second
hydrophilic excipient selected from the group consisting of starch,
microcrystalline cellulose, hydroxypropylcellulose and lactose; and
[0034] (3) a disintegrant selected from the group consisting of
sodium starch glycolate, croscarmellose sodium, low substituted
hydroxypropylcellulose and crospovidone; and
[0035] (ii) a disintegrant selected from the group consisting of
sodium starch glycolate, croscarmellose sodium, low substituted
hydroxypropylcellulose and crospovidone, which is mixed with the
granule of (i).
[0036] In one embodiment of the present invention, the content of
the carbamate compound is 2.5 to 25 wt % based on the total weight
of the orally disintegrating tablet.
[0037] In one embodiment of the present invention, the content of
the hydrophilic excipient is 65 to 90 wt % based on the total
weight of the orally disintegrating tablet.
[0038] In one embodiment of the present invention, the weight ratio
of the first hydrophilic excipient and the second hydrophilic
excipient is 2:1 to 10:1, and preferably 4:1 to 8:1.
[0039] In one embodiment of the present invention, the content of
the disintegrant in the granule of (i) is 1 to 10 wt %, and
preferably 2 to 5 wt % based on the total weight of the orally
disintegrating tablet.
[0040] In one embodiment of the present invention, the disintegrant
mixed in (ii) contains 60 to 80% of particles having a particle
size of 40 to 600 .mu.m, and the content thereof is 4 to 8 wt %
based on the total weight of the orally disintegrating tablet.
[0041] In one embodiment of the present invention, the orally
disintegrating tablet is used for the treatment of anxiety,
depression, convulsion, epilepsy, migraine, bipolar disorder, drug
abuse, smoking, attention deficit hyperactivity disorder (ADHD),
obesity, sleep disorders, neuropathic pain, stroke, cognitive
disorders, neurodegeneration or muscle spasm.
[0042] In addition, the present invention provides a method for
preparation of an orally disintegrating tablet, comprising:
[0043] (a) a step of mixing the following ingredients (1) to (3);
[0044] (1) a carbamate compound of the following Formula 1, an
isomer thereof, or a pharmaceutically acceptable salt, solvate or
hydrate thereof as an active ingredient; [0045] (2) a hydrophilic
excipient consisting of a first hydrophilic excipient of a sugar
alcohol; and a second hydrophilic excipient selected from the group
consisting of starch, microcrystalline cellulose,
hydroxypropylcellulose and lactose; and [0046] (3) a
disintegrant;
[0047] (b) a step of preparing a granule by wet granulation using
the mixture of step (a);
[0048] (c) a step of mixing the granule obtained from step (b) with
a disintegrant; and
[0049] (d) a step of lubricating and tableting the mixture obtained
from step (c):
##STR00005##
[0050] wherein,
[0051] R.sub.1 and R.sub.2 are each independently selected from the
group consisting of hydrogen, halogen, C.sub.1-C.sub.8 alkyl,
halo-C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 thioalkoxy and
C.sub.1-C.sub.8 alkoxy; and one of A.sub.1 and A.sub.2 is CH, and
the other is N.
[0052] In one embodiment of the present invention, in Formula 1,
R.sub.1 and R.sub.2 are each independently selected from the group
consisting of hydrogen, halogen and C.sub.1-C.sub.8 alkyl.
[0053] In one embodiment, the halo-C.sub.1-C.sub.8 alkyl is
perfluoroalkyl.
[0054] In one embodiment of the present invention, the carbamate
compound of Formula 1 is carbamic acid
(R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl ester of the
following Formula 2:
##STR00006##
[0055] In one embodiment of the present invention, the first
hydrophilic excipient of a sugar alcohol is selected from the group
consisting of mannitol, sorbitol, xylitol, lactitol, maltitol and
erythritol.
[0056] In one embodiment of the present invention, the disintegrant
in step (a) and step (c) is selected from the group consisting of
sodium starch glycolate, croscarmellose sodium, low substituted
hydroxypropylcellulose and crospovidone.
[0057] Accordingly, in one embodiment, the present invention
provides a method for preparation of an orally disintegrating
tablet, comprising:
[0058] (a) a step of mixing the following ingredients (1) to (3);
[0059] (1) a carbamate compound of Formula 1, an isomer thereof, or
a pharmaceutically acceptable salt, solvate or hydrate thereof as
an active ingredient; [0060] (2) a hydrophilic excipient consisting
of a first hydrophilic excipient of a sugar alcohol selected from
the group consisting of mannitol, sorbitol, xylitol, lactitol,
maltitol and erythritol; and a second hydrophilic excipient
selected from the group consisting of starch, microcrystalline
cellulose, hydroxypropylcellulose and lactose; and [0061] (3) a
disintegrant selected from the group consisting of sodium starch
glycolate, croscarmellose sodium, low substituted
hydroxypropylcellulose and crospovidone;
[0062] (b) a step of preparing a granule by wet granulation using
the mixture of step (a);
[0063] (c) a step of mixing the granule obtained from step (b) with
a disintegrant selected from the group consisting of sodium starch
glycolate, croscarmellose sodium, low substituted
hydroxypropylcellulose and crospovidone; and
[0064] (d) a step of lubricating and tableting the mixture obtained
from step (c).
[0065] In one embodiment of the present invention, the content of
the carbamate compound is 2.5 to 25 wt % based on the total weight
of the orally disintegrating tablet.
[0066] In one embodiment of the present invention, the content of
the hydrophilic excipient is 65 to 90 wt % based on the total
weight of the orally disintegrating tablet.
[0067] In one embodiment of the present invention, the weight ratio
of the first hydrophilic excipient and the second hydrophilic
excipient is 2:1 to 10:1, and preferably 4:1 to 8:1.
[0068] In one embodiment of the present invention, the content of
the disintegrant in step (a) is 1 to 10 wt %, and preferably 2 to 5
wt % based on the total weight of the orally disintegrating
tablet.
[0069] In one embodiment of the present invention, the disintegrant
in step (c) contains 60 to 80% of particles having a particle size
of 40 to 600 .mu.m, and the content thereof is 4 to 8 wt % based on
the total weight of the orally disintegrating tablet.
[0070] The present invention also provides an orally disintegrating
tablet prepared by the above method.
[0071] In one embodiment of the present invention, the orally
disintegrating tablet is used for the treatment of anxiety,
depression, convulsion, epilepsy, migraine, bipolar disorder, drug
abuse, smoking, attention deficit hyperactivity disorder (ADHD),
obesity, sleep disorders, neuropathic pain, stroke, cognitive
disorders, neurodegeneration or muscle spasm.
Effect of the Invention
[0072] The orally disintegrating tablet according to the present
invention can be administered to patients suffering from discomfort
and difficulty in swallowing the carbamate compound of Formula 1 or
2, thereby increase the patients' medication compliance. In
particular, it is possible to administer the drug to patients with
epilepsy who need to prevent further seizures by maintaining the
blood concentration of the drug above the therapeutic
concentration, so that the recurrence of further seizures can be
prevented, and severe nerve damage and after-effects can be
prevented. The orally disintegrating tablet prepared by the method
according to the present invention exhibits excellent storage
stability due to its high hardness and low friability, exhibits a
rapid disintegration rate in the oral cavity and has excellent
effect of having little foreign body sensation and residual
feeling.
BRIEF DESCRIPTION OF THE DRAWINGS
[0073] FIG. 1 is results of the dissolution test in Experimental
Example 1 using the tablets prepared in Example 1 and Comparative
Example 1.
[0074] FIG. 2 is results of the hygroscopicity measurement test in
Experimental Example 3 using the tablets prepared in Example 2 and
Comparative Example 2.
[0075] FIG. 3 is results of the wetting time test in Experimental
Example 3 using the tablets prepared in Example 2 and Comparative
Example 2.
[0076] FIG. 4 is results of the test for change of tablet due to
pressure in the oral cavity in Experimental Example 3 using the
tablets prepared in Example 2 and Comparative Example 2.
[0077] FIG. 5 is photos of disintegration of the tablets in
artificial saliva in Experimental Example 4 using the tablets
prepared in Example 1 and Comparative Example 1, and the resulting
disintegrated solutions.
[0078] FIG. 6 is electron micrographs of the resulting
disintegrated solutions of the tablets in artificial saliva in
Experimental Example 4 using the tablets prepared in Example 2 and
Comparative Example 2.
DETAILED DESCRIPTION
[0079] Hereinafter, the present invention will be described in
detail.
[0080] One embodiment of the present invention relates to an orally
disintegrating tablet comprising:
[0081] (i) a granule prepared by wet granulation to comprise the
following ingredients: [0082] (1) a carbamate compound of the
following Formula 1, an isomer thereof, or a pharmaceutically
acceptable salt, solvate or hydrate thereof as an active
ingredient; [0083] (2) a hydrophilic excipient consisting of a
first hydrophilic excipient of a sugar alcohol; and a second
hydrophilic excipient selected from the group consisting of starch,
microcrystalline cellulose, hydroxypropylcellulose and lactose; and
[0084] (3) a disintegrant; and
[0085] (ii) a disintegrant which is mixed with the granule of
(i):
##STR00007##
[0086] wherein,
[0087] R.sub.1 and R.sub.2 are each independently selected from the
group consisting of hydrogen, halogen, C.sub.1-C.sub.8 alkyl,
halo-C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 thioalkoxy and
C.sub.1-C.sub.8 alkoxy; and one of A.sub.1 and A.sub.2 is CH, and
the other is N.
[0088] Another embodiment of the present invention relates to a
method for preparation of an orally disintegrating tablet,
comprising:
[0089] (a) a step of mixing the following ingredients (1) to (3);
[0090] (1) a carbamate compound of Formula 1, an isomer thereof, or
a pharmaceutically acceptable salt, solvate or hydrate thereof as
an active ingredient; [0091] (2) a hydrophilic excipient consisting
of a first hydrophilic excipient of a sugar alcohol; and a second
hydrophilic excipient selected from the group consisting of starch,
microcrystalline cellulose, hydroxypropylcellulose and lactose; and
[0092] (3) a disintegrant;
[0093] (b) a step of preparing a granule by wet granulation using
the mixture of step (a);
[0094] (c) a step of mixing the granule obtained from step (b) with
a disintegrant; and
[0095] (d) a step of lubricating and tableting the mixture obtained
from step (c).
[0096] In one embodiment of the present invention, in Formula 1,
R.sub.1 and R.sub.2 are each independently selected from the group
consisting of hydrogen, halogen and C.sub.1-C.sub.8 alkyl.
[0097] In one embodiment of the present invention, the
halo-C.sub.1-C.sub.8 alkyl is perfluoroalkyl.
[0098] In one embodiment of the present invention, the carbamate
compound of Formula 1 is carbamic acid
(R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl ester of the
following Formula 2:
##STR00008##
[0099] The term "compound" or "active ingredient" is a concept that
encompasses not only the compound itself but also its isomers, or
pharmaceutically acceptable salts, solvates and hydrates thereof
altogether. Accordingly, as used herein, the carbamate compound of
Formula 1 refers to not only the compound but also its isomers, or
pharmaceutically acceptable salts, solvates or hydrates thereof.
Likewise, as used herein, the carbamate compound of Formula 2
refers to not only the carbamic acid
(R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl ester but also its
isomers, or pharmaceutically acceptable salts, solvates or hydrates
thereof.
[0100] Examples of the pharmaceutically acceptable salts of the
carbamate compound of Formula 1 include independently, acetate,
benzenesulfonate, benzoate, bitartrate, calcium acetate, camsylate,
carbonate, citrate, edetate, edisylate, estolate, esylate,
fumarate, gluceptate, gluconate, glutamate, glycoloyl arsanilate,
hexylresorcinate, hydravamine, hydrobromide, hydrochloride,
hydrogencarbonate, hydroxynaphthoate, iodide, isethionate, lactate,
lactobionate, malate, maleate, mandelate, mesylate, methylnitrate,
methylsulfate, mucate, napsylate, nitrate, pamoate (embonate),
pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,
stearate, subacetate, succinate or hemi-succinate, sulfate or
hemi-sulfate, tannate, tartrate, oxalate or hemi-tartrate,
teoclate, triethiodide, benzathine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine, procaine, aluminum,
ammonium, tetramethylammonium, calcium, lithium, magnesium,
potassium, sodium and zinc, etc.
[0101] A person having ordinary skill in the art of synthesis of
compounds could have easily prepared the carbamate compound of
Formula 1 or 2 using known compounds or compounds which can be
easily prepared therefrom. In particular, methods for preparing the
compound of Formula 1 are described in detail in PCT Publication
Nos. WO 2006/112685 A1, WO 2010/150946 A1 and WO 2011/046380 A2,
the disclosures of which are incorporated herein by reference. The
compound of Formula 1 can be chemically synthesized by any of the
methods described in the above documents, but the methods are
merely exemplary ones, and the order of the unit operation and the
like may be selectively changed if necessary. Hence, the above
methods are not intended to limit the scope of the invention.
[0102] Specifically, the orally disintegrating tablet may comprise
the carbamate compound of Formula 1 or 2 in an amount of 2.5 to 25
wt %, or 5 to 10 wt % per tablet. In another embodiment, the orally
disintegrating tablet of the present invention may comprise said
active ingredient in an amount of 1 to 30 mg, or 10 to 20 mg.
[0103] In one embodiment of the present invention, the orally
disintegrating tablet comprises granules prepared by wet
granulation method and a disintegrant mixed with the granules.
[0104] The method for preparing the orally disintegrating tablet
comprises a step of preparing granules by wet granulation method
and a step of mixing the granules obtained in the above step with a
disintegrant. Specifically, a carbamate compound of Formula 1, a
hydrophilic excipient and a disintegrant are mixed with water and
the mixture is granulated. The wet-granules can then be dried.
[0105] The type and amount of the hydrophilic excipient added in
the wet granulation step is very important. If the hydrophilic
excipient has a high molecular weight or a high viscosity, the
excipient forms a high-viscosity gel when it is hydrated by saliva
in the oral cavity. In this case, it is difficult to achieve rapid
disintegration in the oral cavity and there may be an unpleasant
feeling in the oral cavity.
[0106] The hydrophilic excipient comprises a first hydrophilic
excipient of a sugar alcohol; and a second hydrophilic excipient
selected from the group consisting of starch, microcrystalline
cellulose, hydroxypropylcellulose and lactose. The content of the
hydrophilic excipient may be 65 to 90 wt %, and specifically 75 to
85 wt % based on the total weight of the orally disintegrating
tablet.
[0107] In one embodiment of the present invention, the first
hydrophilic excipient of a sugar alcohol may be one or more
selected from the group consisting of mannitol, sorbitol, xylitol,
lactitol, maltitol and erythritol. Specifically, it may be
mannitol.
[0108] In one embodiment of the present invention, examples of the
starch in the second hydrophilic excipient include corn starch,
pregelatinized starch, potato starch, wheat starch, glutinous rice
starch, sweet potato starch, tapioca starch, rice starch, waxy corn
starch, and the like, but they are not limited thereto. In one
embodiment of the present invention, the second hydrophilic
excipient may be pregelatinized starch.
[0109] In one embodiment of the present invention, the hydrophilic
excipient may be a mixture of a sugar alcohol and starch, and more
specifically a mixture of mannitol and starch, but it is not
limited thereto. The orally disintegrating tablet of the present
invention may be prepared by combining two or more of other
hydrophilic excipients having properties similar to that of each
selected from the first hydrophilic excipient and the second
hydrophilic excipient.
[0110] In one embodiment of the present invention, the weight ratio
of the first hydrophilic excipient and the second hydrophilic
excipient may be 2:1 to 10:1, specifically 4:1 to 8:1, and more
specifically 5:1 to 7:1. By appropriately adjusting the ratio of
the first hydrophilic excipient and the second hydrophilic
excipient, it is possible to prepare an orally disintegrating
tablet that is capable of rapidly disintegrating in the oral cavity
and has an excellent hardness and friability.
[0111] In order to prepare an orally disintegrating tablet capable
of rapidly disintegrating in the oral cavity, the appropriate
composition and amount of the first disintegrant added in the step
of wet granulation and the second disintegrant added in the step of
mixing with granules are important. The first disintegrant added in
the step of wet granulation may be the same as or different from
the second disintegrant added in the step of mixing with
granules.
[0112] The disintegrant as the first disintegrant added in the step
of wet granulation or added in granules may be one or more selected
from the group consisting of sodium starch glycolate,
croscarmellose sodium, low substituted hydroxypropylcellulose and
crospovidone. Specifically, it may be sodium starch glycolate. The
content of the disintegrant is 1 to 10 wt %, and specifically 2 to
5 wt % based on the total weight of the orally disintegrating
tablet.
[0113] In one embodiment, during the above wet granulation step,
the hydrophilic excipient can be mixed after the active ingredient
and the disintegrant are mixed.
[0114] In one embodiment, wet granule and the second disintegrant
may be dry-blended.
[0115] The disintegrant as the second disintegrant added in the
step of mixing with granules may be one or more selected from the
group consisting of sodium starch glycolate, croscarmellose sodium,
low substituted hydroxypropylcellulose and crospovidone.
Specifically, it may be crospovidone. The content of the
disintegrant is preferably 4 to 8 wt % based on the total weight of
the orally disintegrating tablet. The disintegrant, which is added
during the step of mixing with granules, may contain 60 to 80% of
particles having a particle size of 40 to 600 .mu.m. Among them, at
least 80% of particles may have a size of 40 to 100 .mu.m. If the
disintegrant satisfying said conditions is selected, it is possible
to prepare an orally disintegrating tablet having minimized foreign
body sensation and residual feeling, high hardness and low
friability.
[0116] In one embodiment of the present invention, the orally
disintegrating tablet may contain about 2.5 to 25 wt %, about 3 to
20 wt %, or about 5 to 10 wt % of the carbamate compound of Formula
1; about 65 to 90 wt %, or about 75 to 85 wt % of the hydrophilic
excipient; and about 5 to 18 wt %, or about 6 to 13 wt % of the
disintegrant based on the total weight of the tablet.
[0117] The orally disintegrating tablet may comprise a lubricant, a
glidant and a sweetening agent, etc.
[0118] In one embodiment of the present invention, magnesium
stearate, calcium stearate, zinc stearate, talc, wax, boric acid,
hydrogenated vegetable oil, sodium chlorate, magnesium lauryl
sulfate, sodium oleate, sodium acetate, sodium benzoate,
polyethylene glycol, stearic acid, fatty acid, sodium stearyl
fumarate, sodium lauryl sulfate and mixtures thereof may be used as
an appropriate lubricant, but it is not limited thereto.
Preferably, the lubricant is magnesium stearate or sodium lauryl
sulfate. The content of the lubricant may be 0.1 to 5 wt % based on
the total weight of the orally disintegrating tablet.
[0119] In one embodiment of the present invention, silica;
colloidal silicon dioxide and talc, etc. may be used as an
appropriate glidant, but it is not limited thereto.
[0120] In one embodiment of the present invention, aspartame,
potassium acesulfame, sodium saccharinate, neohesperidin
dihydrochalcone, sucralose, saccharin, sugars (for example,
sucrose, glucose, lactose and fructose), a sugar alcohol (for
example, mannitol, sorbitol, xylitol and erythritol) and mixtures
thereof may be used as an appropriate sweetener, but it is not
limited thereto. Preferably, the sweetener is aspartame, sucralose
and/or saccharin. The content of the sweetener may be 0.1 to 5 wt
%, and preferably 0.2 to 3 wt % based on the total weight of the
orally disintegrating tablet.
[0121] A flavoring agent and a pigment preservative agent, etc. may
be further added as other additives.
[0122] The orally disintegrating tablet may be disintegrated in the
oral cavity within 60 seconds or 30 seconds, and specifically
within 20 seconds when measured according to the disintegration
test of Korean Pharmacopeia (11th edition).
[0123] In addition, from the orally disintegrating tablet, at least
80% of the active ingredient may be eluted within 10 minutes, or at
least 90% of the active ingredient may be eluted within 15 minutes
when eluted by the No. 2 method (Paddle method, apparatus 2) with
the dissolution test No. 1 solution (900 ml), at 50 revolutions/min
at 37.degree. C. according to Korean Pharmacopeia (11th
edition).
[0124] In addition, the hardness and the friability of the orally
disintegrating tablet may be measured in a conventional manner. As
a result of measurement in such a manner, the hardness is 6 to 12
kp and the friability is 1.0% or less, which means a high storage
stability. Specifically, since the hardness is 9 to 11 kp and the
friability is 0.6% or less, the storage stability is high.
[0125] The orally disintegrating tablet may be used for the
treatment of anxiety, depression, convulsion, epilepsy, migraine,
bipolar disorder, drug abuse, smoking, attention deficit
hyperactivity disorder (ADHD), obesity, sleep disorders,
neuropathic pain, stroke, cognitive disorders, neurodegeneration or
muscle spasm.
[0126] The dosage of the carbamate compound of Formula 1 or 2 for
the prevention, alleviation or treatment of the above diseases may
typically vary depending on the severity of the disease, the body
weight and the metabolic status of the subject. A "therapeutically
effective amount" for an individual patient refers to an amount
sufficient to achieve a therapeutic effect. Specifically, the
therapeutically effective amount of the compounds of the present
invention is 50 to 500 mg, 50 to 400 mg, 50 to 300 mg, 100 to 400
mg, 100 to 300 mg, 50 to 200 mg, or 100 to 200 mg, based on the
free form and once-daily administration to humans. The
therapeutically effective amount is preferably 50 to 300 mg, more
preferably 50 to 200 mg.
[0127] The usage and dosage of the orally disintegrating tablet of
the present invention are determined depending on the patient's
gender, age and other conditions, the disease state and the like.
In one embodiment, the orally disintegrating tablet of the present
invention may be administered twice to four times a day at 4 to 12
hour intervals, and the dosage and interval may be adjusted as
necessary.
[0128] The orally disintegrating tablet prepared by the method
according to the present invention exhibits excellent storage
stability due to its high hardness and low friability, exhibits a
rapid disintegration rate in the oral cavity at the same time, and
has excellent effect of having little foreign body sensation and
residual feeling. This is made possible by the appropriate
combination and amount of the two types of hydrophilic excipients
and by the appropriate combination of the disintegrant. In
addition, the wet granulation method, which is a relatively simple
and economical method, is used to minimize foreign body sensation
and residual feeling.
[0129] Hereinafter, the present invention will be explained in more
detail through working examples. However, the following working
examples are only intended to illustrate one or more embodiments
and are not intended to limit the scope of the invention.
EXAMPLES
Preparation Example
Synthesis of carbamic acid
(R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl ester
[0130] Carbamic acid (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl
ester (the compound of Formula 2, hereinafter referred to as "the
test compound") was prepared according to the method described in
Preparation Example 50 of PCT Publication No. WO 2010/150946.
Examples 1 and 2
Preparation of Orally Disintegrating Tablets
[0131] Carbamic acid (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl
ester and sodium starch glycolate were mixed in a composition as
shown in Table 1 below and sieved through a 30 mesh sieve. Mannitol
and pregelatinized starch were mixed and the mixture was sieved
through a 30 mesh sieve, which was used previously, to wash the
sieve. An appropriate amount of purified water was added to the
mixture. The granule mixture was dried in an oven at 60.degree. C.
for 1 hour, crospovidone was added thereto, and then they were
dry-blended. After the dry post-mix was completed, magnesium
stearate was sieved thereto with a 40 mesh sieve to lubricate. And
then, the mixture was tableted with a single-punch tablet press
(ERWEKA) to prepare an orally disintegrating tablet of 200 mg dose
per tablet.
TABLE-US-00001 TABLE 1 Compositions of the tablets of Examples 1
and 2 Example 1 Example 2 Ingredients wt % wt % Carbamic acid
(R)-1-(2- 5.0 10.0 chlorophenyl)-2-(tetrazol-2-yl)ethyl ester
Mannitol 69.75 67.25 Pregelatinized starch 12.5 10 Sodium starch
glycolate 4.5 4.5 Purified water 1.2 mL per tablet 1.0 mL per
tablet Crospovidone 6.35 6.35 Magnesium stearate 0.9 0.9 Flavoring
agent 1.0 1.0 Total 100 100
Comparative Examples 1 and 2
Preparation of Immediate-Release Tablets
[0132] Carbamic acid (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl
ester and colloidal silicon dioxide were mixed in the composition
as shown in Table 2 below and sieved through a 30 mesh sieve.
Microcrystalline cellulose, lactose monohydrate and sodium starch
glycolate were mixed and the mixture was sieved through a 30 mesh
sieve, which was used previously, to wash the sieve, and then
mixed. Magnesium stearate was sieved through a 40 mesh sieve and
added to the mixture to lubricate. And then, the mixture was
tableted with a single-punch tablet press (ERWEKA) to prepare an
immediate-release tablet of 200 mg dose per tablet.
TABLE-US-00002 TABLE 2 Compositions of the tablets of Comparative
Examples 1 and 2 Comparative Comparative Example 1 Example 2
Ingredients wt % wt % Carbamic acid (R)-1-(2- 5.0 10.0
chlorophenyl)-2-(tetrazol-2-yl)ethyl ester Microcrystalline
cellulose 53.07 48.07 Lactose monohydrate 35.25 35.25 Sodium starch
glycolate 4.5 4.5 Colloidal silicon dioxide 1.0 1.0 Magnesium
stearate 1.18 1.18 Total 100 100
Experimental Example 1
Dissolution and Disintegration Test and Evaluation
[0133] a. Dissolution Test
[0134] Each of the orally disintegrating tablets prepared in
Example 1 and the immediate-release tablets prepared in Comparative
Example 1 was tested and evaluated by the apparatus and the tester
described in dissolution test in the Korean Pharmacopeia (11th
edition). The test was carried out under No. 2 test (Paddle method,
apparatus 2) with the dissolution test No. 1 solution (900 ml), at
50 revolutions/min at 37.degree. C. As a result, Example 1 and
Comparative Example 1 showed the same dissolution results. The
resulting graph is shown in FIG. 1.
[0135] b. Disintegration Test
[0136] The orally disintegrating tablets and the immediate-release
tablets prepared in Examples 1 and 2, and Comparative Examples 1
and 2, respectively, were tested in No. 1 solution with the
apparatus and the tester described in the disintegration test in
the Korean Pharmacopeia (11th edition), and six (6) test results
were averaged. The results are shown in Table 3 below.
TABLE-US-00003 TABLE 3 Results of the disintegration test
Disintegration rate (sec) Comparative Example 1 31 Comparative
Example 2 35 Example 1 15 Example 2 14
[0137] As shown in Table 3, the orally disintegrating tablets of
Examples 1 and 2 showed a much faster disintegration rate than the
immediate-release tablets of Comparative Examples 1 and 2.
Experimental Example 2
Evaluation of Ease of Movement and Storage of the Tablets
[0138] Measurement of Hardness and Friability
[0139] The hardness of the tablet was determined by using HDT-300
of LOGAN INSTRUMENT CORP. for each of six (6) tablets, and the
average value was recorded. The friability of the tablet was
determined by using FRIABILATOR of KUKJE ENG. CO. and the results
were recorded by averaging the results of three trials conducted on
a set of ten tablets. The results of the test are shown in Table 4
below.
TABLE-US-00004 TABLE 4 Results of measurement of hardness and
friability Hardness (kp) Friability (%) Comparative Example 1 14.1
0.41 Comparative Example 2 13.3 0.28 Example 1 10.4 0.54 Example 2
10.6 0.32
[0140] As shown in Table 4, the orally disintegrating tablets of
Examples 1 and 2 showed hardness and friability comparable to those
of the immediate-release tablets of Comparative Examples 1 and 2,
despite their property of immediate disintegration in the oral
cavity.
Experimental Example 3
Evaluation of Possibility of Disintegration in the oral-mimic
condition
[0141] a. Hygroscopicity Measurement
[0142] To simulate the oral environment, the interior of the
desiccator was saturated with a supersaturated solution of
potassium hydrogen phosphate to form a condition of relative
humidity of 95%. The tablets of Example 2 and Comparative Example 2
were put in said desiccator of relative humidity of 95% without
packing, and change was observed. As a result, the tablet of
Comparative Example 2 showed no change caused by external humidity.
In contrast, the surface of the tablet of Example 2 was roughened
and swollen by humidification. Therefore, it was anticipated that
the tablet of Example 2 would be rapidly disintegrated in the
high-humidity oral condition in which saliva is present (see FIG.
2).
[0143] b. Tests for Measurement of Wetting Time and Determination
of Change of Tablet Due to Pressure
[0144] The tissues were spread on a chalet and wetted with
artificial saliva. Then the tablets of Example 2 and Comparative
Example 2 were each placed thereon, and the time during which the
tablet was completely wetted was measured. In addition, the same
pressure was applied to each tablet which was completely wet, and
their state was observed.
[0145] As a result of the test, in the tablet of Example 2, the
entire tablet was wet and swollen in 45 seconds. In contrast, the
tablet of Comparative Example 2 did not wet as a whole even after
60 seconds (see FIG. 3). In addition, as a result of applying the
same pressure using a spoon, the tablet of Comparative Example 2
was pressed while maintaining the tablet shape (see the photo on
the left of FIG. 4), but the shape of the tablet of Example 2 was
completely destroyed (see the photo on the right of FIG. 4).
[0146] Therefore, it was anticipated that when the tablet is
exposed to high-humidity conditions in the oral cavity after
ingestion and is then subjected to pressure by the roof of the
mouth, the tablets of Example 2 would show excellent
disintegrability.
Experimental Example 4
Evaluation of Possibility of Foreign Body Sensation and Residual
Feeling
[0147] Microscopic Measurement of Solution Resulting from
Disintegration in Artificial Saliva
[0148] The tablets of Example 2 and Comparative Example 2 were each
put into artificial saliva, and their disintegration was observed.
After disintegration, the solution was taken and magnified 50 times
and 200 times with a microscope (OLYMPUS) for evaluating the
possibility of foreign body sensation and residual feeling. As a
result, in the case of the tablet of Comparative Example 2, a
particle size of 100 .mu.m or more was observed. In case of the
tablet of Example 2, however, a particle size of several .mu.m was
observed, which indicates that there will be almost no foreign body
sensation and residual feeling (see FIGS. 5 and 6).
* * * * *